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Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2
A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carrie...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Phytochemical Society of Europe. Published by Elsevier Ltd.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343747/ https://www.ncbi.nlm.nih.gov/pubmed/35935343 http://dx.doi.org/10.1016/j.phytol.2022.07.010 |
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author | Tret’yakova, Elena V. Ma, Xinyuan Kazakova, Oxana B. Shtro, Anna A. Petukhova, Galina D. Klabukov, Artem M. Dyatlov, Danil S. Smirnova, Anna A. Xu, Huan Xiao, Sulong |
author_facet | Tret’yakova, Elena V. Ma, Xinyuan Kazakova, Oxana B. Shtro, Anna A. Petukhova, Galina D. Klabukov, Artem M. Dyatlov, Danil S. Smirnova, Anna A. Xu, Huan Xiao, Sulong |
author_sort | Tret’yakova, Elena V. |
collection | PubMed |
description | A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC(50) values ranged from 0.19 to 5.0 μM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds 12 and 21 bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0–10 and 1–10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound 12 into the binding pocket of influenza A virus M2 protein. Compound 9 with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC(50) of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds. |
format | Online Article Text |
id | pubmed-9343747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Phytochemical Society of Europe. Published by Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93437472022-08-02 Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 Tret’yakova, Elena V. Ma, Xinyuan Kazakova, Oxana B. Shtro, Anna A. Petukhova, Galina D. Klabukov, Artem M. Dyatlov, Danil S. Smirnova, Anna A. Xu, Huan Xiao, Sulong Phytochem Lett Article A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC(50) values ranged from 0.19 to 5.0 μM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds 12 and 21 bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0–10 and 1–10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound 12 into the binding pocket of influenza A virus M2 protein. Compound 9 with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC(50) of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds. Phytochemical Society of Europe. Published by Elsevier Ltd. 2022-10 2022-08-02 /pmc/articles/PMC9343747/ /pubmed/35935343 http://dx.doi.org/10.1016/j.phytol.2022.07.010 Text en © 2022 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Tret’yakova, Elena V. Ma, Xinyuan Kazakova, Oxana B. Shtro, Anna A. Petukhova, Galina D. Klabukov, Artem M. Dyatlov, Danil S. Smirnova, Anna A. Xu, Huan Xiao, Sulong Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title | Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title_full | Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title_fullStr | Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title_full_unstemmed | Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title_short | Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2 |
title_sort | synthesis and evaluation of diterpenic mannich bases as antiviral agents against influenza a and sars-cov-2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343747/ https://www.ncbi.nlm.nih.gov/pubmed/35935343 http://dx.doi.org/10.1016/j.phytol.2022.07.010 |
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